Infection with Human Herpesvirus 8 (HHV-8) is common worldwide, but is found most often among men who have sex with men (MSM) in the United States (US). Despite over a decade of behavioral and biologic studies, the mode of transmission and risk factors for infection with HHV-8 among MSM remains unknown, largely because almost all studies are cross-sectional in nature. Previous work has shown that HHV-8 shedding is most frequent in the oropharynx, oral epithelial cells are competent sites for HHV-8 replication, and the behavior of "deep kissing" is associated with HHV-8 infection. Genital shedding of the virus occurs less frequently, yet sexual behaviors with exposure to genital secretions have been correlated with HHV-8 infection. This application will focus on defining the mode(s) of transmission of HHV-8 among MSM. We hypothesize that: HHV-8 is primarily transmitted through saliva, albeit the efficiency of transmission from oral genital contact may be less than genital contact. We will explore these hypotheses using two approaches. First, we will use a prospective cohort study of MSM couples who are discordant in their HHV-8 serostatus (one HHV-8 seropositive, one HHV-8 seronegative). The seropositive partner will be evaluated for HHV-8 oral and genital shedding, and details of sexual behavior will be collected. The seronegative partner will be followed with regular serologic assays and virologic assessment of shedding to determine the time of infection with HHV-8. Second, we will longitudinally follow a cohort of MSM for new cases of HHV-8 seroconversion. A contact investigation will recruit recent sexual partners of incident cases to assess their oropharyngeal and genital HHV-8 shedding patterns, in addition to collecting details of sexual behavior. The relationship between HHV-8 oropharyngeal shedding and HHV-8 transmission will be analyzed using a novel combination of molecular epidemiology and a case-control study that has recently been validated with herpes simplex virus type 2. The importance of genital shedding in the transmission of HHV-8 will be determined by comparing the partners of all cases of HHV-8 infection identified in both cohorts to the partners of persistently persons from the discordant couple cohort. Using logistic regression, we will estimate the odds of an incident case having a partner who sheds HHV-8 from the genital tract. These two studies will provide data on the association between the anatomic site and quantity of HHV-8 shedding and transmission.